Sepsis is defined as a systemic inflammatory response syndrome associated with infection [Bone RC: Ann. Intern. Med. 115, 457 (1991)], and first begins with an excess invasion of Gram-negative bacteria, that are causative bacteria of sepsis, or an endotoxin, which is a cell wall constituent component thereof, from a primary lesion into the blood, and distribution thereof throughout the body via the circulatory system. The endotoxin is a lipopolysaccharide (LPS) present in bacterial outer membrane, which is released by the death of Gram-negative bacteria. It stimulates inflammatory cells such as macrophage, neutrophil, lymphocyte and the like and vascular endothelial cell in an organism to cause production of inflammatory cytokines (IL-1, IL-6, IL-8 and the like) including TNF α (tumor necrosis factor α). Such remarkable increase in the inflammatory cytokines causes severe multiple organ dysfunction syndrome (MODS) and often results in the death of organisms.
The chemotherapy of sepsis essentially requires the first use of antibiotics for the eradication of infectious bacteria. In General, administration of antibiotics is most commonly used in parallel with chemotherapy or surgical treatment of complications, in view of the high probability of sequential complications [Fujii et al., Pharmaceutical agent Journal, 34, 1501 (1998)]. As is clear from the fact that lethality due to sepsis has not decreased since 1980s, however, these treatment methods are considered to have reached the limit.
In recent years, anti-cytokine therapies targeting inflammatory cytokines such as TNF α and the like have been actively tried as a new sepsis treatment method. However, effectiveness thereof has not been confirmed in clinical tests of TNF α neutralizing antibody, soluble TNF α receptor and IL-1 receptor antagonist and the like [Gou Wakabayashi et al., Igaku no Ayumi Bessatsu, 108 (1998)]. The targeted inflammatory cytokine is considered to be harmful when it exists in excess but necessary for biological protection as long as it is produced in a certain level of amount.
That is, it means that a complete control of biological activity of cytokine may conversely exacerbate the lesion depending on the stages of disease state of septic patients, which is considered to have been reflected in these clinical achievements [Masahiko Hirota et al., Nihon Gekagakkai Zasshi 100: 667-673 (1999), Gou Wakabayashi et al., Nihon Gekagakkai Zasshi 100: 674-678 (1999)].
In addition, while the endotoxin removing column developed as a medical material has been confirmed to be clinically effective [Kazuhiko Hanazawa et al., ICU and CCU, 197 (1999)], it is expensive and use thereof within the range insurance policy can cover is limited. The foregoing facts suggest importance of endotoxin in the disease state of sepsis, and teach that a low-molecular compound that inhibits endotoxin per se located at the upstream of various inflammatory cytokines including TNF α is a promising new agent for the prophylaxis or treatment of sepsis.
Heretofore, hydroxamic acid derivatives have been studied as MMP (matrix metalloproteinase) inhibitors, and many of such inhibitors have been reported to have an inhibitory action on inflammatory cytokines, particularly TNF α. Many of these have been studied as an agent for the prophylaxis or treatment of sepsis (e.g., WO94/10990 etc.), but have not been clinically applied. In addition, an endotoxin (LPS) inhibitory action by hydroxamic acid derivative has not been reported heretofore.
The present invention has been made in view of the above-mentioned background art, and aims at providing a novel sulfonic acid derivative of hydroxamic acid useful as an LPS inhibitor, and a pharmacologically acceptable salt thereof.
Another object of the present invention is to provide a novel intermediate compound useful for the synthesis of said compound.
A yet another object of the present invention is to provide a novel LPS inhibitor useful as a pharmaceutical agent.